Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been identified. Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e.g., naltrexone and cyclazocine) in humans have limited utility due to poor oral bioavailability and a very rapid clearance rate from the body. This has been shown in many instances to be due to the presence of the 8-hydroxyl group (OH) of 2,6-methano-3-benzazocines, also known as benzomorphans [(e.g., cyclazocine and EKC (ethylketocyclazocine)] and the corresponding 3-OH group in morphinans (e.g., morphine).

Recently morphinans have received renewed attention for the treatment of opioid mediated diseases since the conversion of phenolic C-3 hydroxyl to a carboxamide moiety has been found to improve their bioavailability. (U.S. Pat. Nos. 6,784,187; 6,887,998; 7,265,226, 7,057,035; 7,262,298; U.S. Patent Publication No. 20070021457). However, challenges to producing carboxamide substituted morphinans, particularly in large scale processes, remain.
A common method for the synthesis of carboxamide substituted morphinans involves the conversion of morphinans with C-3-hydroxyl group to a triflate group followed by palladium catalyzed replacement of triflate with cyanide group, and conversion of the cyanide group to a carboxamide group. Wentland et al., Selective Protection and Functionalization of Morphine: Synthesis and Opioid Receptor Binding Properties of 3-Amino-3-desoxymorphine Derivatives, J. Med. Chem., 2000, 43 (19), pp 3558-3565. However, the use of reagents such as triflic anhydride to convert the hydroxyl to a triflate group often leads to side reactions if other functional groups are present. Such side reactions lead to lower yields and make the purification process cumbersome. Furthermore, milder reagents such as N-phenylbis(trifluoromethanesulfonimide) are not suitable for large scale synthesis since such reagents are generally expensive and require laborious processing to remove the by-products that they produce. As such, new methods for synthesizing substituted morphinans, particularly carboxamide substituted morphinans are needed.